Navelbine Injection

(See Table 1.)


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Pharmacotherapeutic group: Cytostatic - Antineoplastic drug.
Pharmacology: Mechanism of action: Navelbine is a cytostatic antineoplastic of the vinca alkaloid group. The molecular target of its activity is tubulin/microtubule dynamic equilibrium. Navelbine inhibits the polymerization of tubulin. lt acts preferentially on mitotic microtubules and affects axonal microtubules only at high concentration.
The effects on tubulin spiralization are Iower than with vincristine. Navelbine blocks mitosis in phase G2+M and induces cell death at interphase or at the following mitosis.

Treatment of non small cell lung cancer.
Treatment of advanced breast cancer in combination with standard chemotherapy.

Strictly by intravenous administration after appropriate dilution. The use of intrathecal route is contra-indicated.
It is recommended to infuse Navelbine over 6-10 minutes after dilution in 20-50 ml of normal saline solution or 5% dextrose solution. Administration should always be followed with at least 250 ml of an isotonic solution infusion to flush the vein.
In monotherapy, the usual dose given is 25-30 mg/m² once weekly.
In combination chemotherapy the dose may be the same while the frequency of administration reduced, i.e.: day 1 and 5 every 3 weeks or day 1 and 8 every 3 weeks according to treatment protocol.
Dose modifications: No dose adjustments are required for renal insufficiency, given the minor renal excretion. If moderate or severe neurotoxicity develops, Navelbine should be discontinued.
The dosage should be adjusted according to hematologic toxicity or hepatic insufficiency, whichever results in the lower dose.
Dose modification for hepatic insufficiency: Navelbine should be administered with caution to patients with hepatic insufficiency. In patients who develop hyperbilirubinemia during treatment with Navelbine, the dose should be adjusted for total bilirubin according to table as follows: (see Table 2.)


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Dose modifications for hematologic toxicity: Granulocyte counts should be ≥1500 cells/mm³ prior to the administration of Navelbine. If the neutrophil count is below 1500/mm³ and/or the platelet count is below 100000/mm³, then the treatment should be delayesd until recovery. Repeat neutrophil count is 1 week. If 3 consecutive weekly doses are held because neutrophil count is <1500 cells/mm³, discontinue Navelbine.
Note: For patients during treatment with Navelbine who have experienced fever and/or sepsis while granulocytopenia or had 2 consecutive weekly doses held due to granulocytopenia, subsequent doses of Navelbine should be: 22.5 mg/m² for granulocytes ≥1500 cells/mm.
Dose modification for concurrent Hematologic toxicity and Hepatic Insufficiency: In patients with both hematologic toxicity and hepatic insufficiency, use the lower of the doses determined from Dose modifications for hematologic toxicity and Dose modifications for hepatic insufficiency.
Administration in the elderly: Clinical experience has not identified relevant differences among elderly patients with regard to the response rate, although greater sensitivity in some of these patients cannot be excluded. Age does not modify the pharmacokinetics of vinorelbine.
Administration in children: Safety and efficacy in children have not been established and administration is therefore not recommended.

Accidental acute overdose have been reported in human: they may produce bone marrow hypoplasia sometimes associated with infection, fever and paralytic ileus. General supportive measures together with blood transfusion and broad spectrum antibiotic therapy should be instituted as deemed necessary by the physician. There is no known antidote for overdose of Navelbine.

Pregnancy, lactation, known hypersensitivity to vinorelbine or other vinca alkaloids, or to any of the constituents., neutrophil count <1500/mm³ or severe infection current or recent (within 2 weeks), platelet count <100000/mm³, in combination with yellow fever vaccine.

Navelbine injection should be administered under the supervision of a physician experienced in the use of chemotherapy. The product is for intravenous (IV) use only. Intrathecal administration of other vinca alkaloids has resulted in death.
Severe granulocytopenia resulting in increased susceptibility to infection may occur. Granulocyte counts should be ≥1500 cells/mm³. Prior to the administration of Navevlbine, the dosage should be adjusted according to complete blood counts with differentials obtained on the day of treatment.
Navelbine must only be administered by the intravenous route.
It is extremely important that the intravenous needle or catheter be properly positioned before any Navelbine is injected. Leakage into surrounding tissue during intravenous administration of Navelbine may cause considerable irritation, local tissue necrosis, and/or thrombophlebitis. If extravasations occur, the injection should be discontinued immediately, and any remaining of the dose should then be introduced into another vein.
Since there are no established guidelines for the treatment of extravasations injuries with Navelbine, institutional guidelines may be used. The ONS chemotherapy guidelines provide additional recommendations for the prevention of extravasations injuries.
Since inhibition of the hematopoietic system is the main risk associated with Navelbine, close haematological monitoring should be undertaken during treatment (determination of hemoglobin level and the leukocyte, neutrophil and platelet counts on the day of each new administration).
The dose limiting adverse reaction is mainly neutropenia. This effect is non-cumulative, having its nadir between 7 and 14 days after the administration and is rapidly reversible within 5 to 7 days.
If the neutrophil count is below 1500/mm³ and/or the platelet count is below 100000/mm³, then the treatment should be delayed until recovery.
The pharmacokinetics of Navelbine is not modified in patients presenting moderate or severe liver impairment. For dosage adjustment in this specific patient group, see "Dose modifications" under Dosage & Administration.
As there is a low level of renal excretion there is no pharmacokinetic rationale for reducing the dose of Navelbine in patients with impaired kidney function.
Navelbine should not be given concomitantly with radiotherapy if the treatment field includes the liver.
All contact with the eyes should be strictly avoided: there is a risk of severe irritation and even corneal ulceration if the drug is sprayed under pressure. Immediate washing of the eye with sodium chloride 9 mg/ml (0.9%) solution for injection should be undertaken if any contact occurs.
Special care should be taken when prescribing for patients with history of ischemic cardiac disease.
If patients present signs or symptoms suggestive of infection, a prompt investigation should be carried out.
Use of this medicine with live attenuated vaccines is not recommended (for yellow fever vaccine, see Contraindications).
Caution is recommended when Navelbine is used with strong inhibitors or inducers of cytochrome CYP3A4. Hence, the use of this medicine with phenytoïn, fosphenytoïn, itraconazole or posaconazole is not recommended.
Patients treated with Navelbine should be frequently monitored for myelosuppression both during and after therapy.
Reported cases of interstitial pulmonary changes and ARDS occurred in patients treated with Navelbine, in combination with mitomycin. The mean time to onset of these symptoms after vinorelbine administration was 1 week (range 3 to 8 days). Patients with alterations in their baseline pulmonary symptoms or with new onset of dyspnoea, cough, hypoxia, or other symptoms should be evaluated promptly.
Navelbine has been reported to cause severe constipation (e.g. grade 3-4) such as paralytic ileus.
If severe adverse events occur, Navelbine should be reduced in dosage or discontinued and appropriate corrective measures taken. Reinstitution of therapy with Navelbine should be carried out with caution and alertness as to possible recurrence of toxicity.
Navelbine should be used in extreme caution in patients whose bone marrow reserve may have been compromised by prior irradiation or chemotherapy, or whose marrow function is recovering from the effects of previous chemotherapy.
Patients with a prior history of pre-existing neuropathy, regardless of etiology, should be monitored for new or worsening signs and symptoms of neuropathy while receiving Navelbine.
Effects on ability to drive and use machines: Navelbine is unlikely to impair the ability of patients to drive or to operate machinery. Nevertheless patients should be advised that their ability to drive and operate machinery may be affected.
Use in children: Safety and efficacy in children have not been established and administration is therefore not recommended.
Use in elderly: Clinical experience has not identified relevant differences among elderly patients with regard to the response rate, although greater sensitivity in some of these patients cannot be excluded. Age does not modify the pharmacokinetics of vinorelbine.

Infections and infestations: Mild to moderate bacterial, viral or fungal infection at different localization (respiratory, urinary, gastrointestinal tract…) are common and usually reversible with an appropriate treatment.
Severe sepsis with other visceral failure and septicaemia occured in less than 1% of patients.
Complicated septicaemia and sometimes fatal are very rare. Neutropenic sepsis have been reported in post-marketing experience.
Haematological tolerance: The limiting toxicity is bone marrow depression resulting mainly neutropenia (G3: 24.3%; G4: 27.8%) which is reversible within 5 to 7 days and noncumulative overtime; neutrophil nadir occurs usually between 7 and 14 days after administration.
Anaemia (G3-4: 7.4%) and thrombocytopenia (G3-4: 2.5%) may occur, but are seldom severe,
Febrile neutropenia have been identified in post-marketing experience.
Immune system disorders: System allergic reactions as anaphylaxis, anaphylactic shock or anaphylactoïd type reaction have been reported in post-marketing experience.
Endocrine disorders: Patients treated by Navelbine have reported an inappropriate antidiuretic hormone secretion (SIADH).
Metabolism and nutrition disorders: Rare cases of severe hyponatraemia have been reported.
Anorexia has been identified as a post-marketing adverse effect.
Neurological tolerance: Neurologic disorders including loss of deep tendon reflexes are very common (in Iess than 5% of patients).
Weakness of the lower extremities has been reported after a prolonged treatment. Severe paresthesias with sensory and motor symptoms are uncommon and generally reversible.
Gastrointestinal tolerance: Constipation is the main symptom (G3-4: 2.7%) which rarely progress to paralytic ileus. Treatment may be resumed after recovery of normal bowel mobility. Stomatitis and diarrhoea usually mild to moderate may occur.
Nausea and vomiting may occur. The incidence of severe effects is low (G3-4: 2.2%). Anti-emetic therapy may reduce their occurence.
Rare cases of pancreatitis have been reported.
Liver: Transient elevations of liver function tests without clinical symptoms were reported.
Skin: Alopecia usually mild in nature may occur.
Rarely Navelbine may produce generalized cutaneous reaction,
Erythema on hands and feet has been reported as a post-marketing adverse effect.
Musculoskeletal and connective tissue disorders: Arthralgia including jaw pain and myalgia have been commonly experienced by patients receiving Navelbine therapy.
Respiratory system: As with other vinca alkaloids, Navelbine may occasionally produce acute shortness of breath, dyspnoea and severe bronchospasm. These adverse events may require treatment with supplemental oxygen, bronchodilators, and/or corticosteroids, particularly when there is pre-existing pulmonary dysfunction.
Rare cases of interstitial pneumopathy have been reported in patients treated with Navelbine in combination with mitomycin.
Cardiovascular system: There have been rare reports of ischemic cardiac disease (angina pectoris, myocardial infarction),
Tachycardia, palpitations and heart rhythm disorders are very rare adverse effects,
Chest pain was reported in 5% of patients. Most reports of chest pain were in patients who had either a history of cardiovascular disease or tumor within the chest.
Vascular disorders: Hypotension, hypertension, flushing and peripheral coldness are uncommon adverse effects. Severe hypotension and collapse are rare.
Local reaction: Like with other vinca alkaloids, Navelbine is a moderate vesicant.
Injection site reactions including erythema, vein discoloration, burning pain and local phlebitis may be observed in approximately one third of patients; 5% were severe.
Chemical phlebitis along the vein proximal to the site of injection was reported in 10% of patients. Bolus injection followed by abundant flushing of the vein can limit this effect. Insertion of a central venous line may be necessary.
Other undesirable effects: Fever, asthenia, fatigue, chest pain and pain at the tumor site have been experienced by patients receiving Navelbine therapy.
Any extravasations may induce local reactions which rarely progress to necrosis (see Precautions).

Acute pulmonary reaction have been reported with Navelbine and other anticancer vinca alkaloids use in conjunction with mitomycin.
Although the Pharmacokinetics of vinorelbine are not influenced by the concurrent administration of cisplatin, the incidence of granulocytopenia with Navelbine used in combination with cisplatin is significantly higher than with single agent Navelbine.
Patients who receive Navelbine and paclitaxel either concomitantly or sequentially, should be monitored for signs and symptoms of neuropathy. Administration of Navelbine to patients with prior or concomitant radiation therapy may result in radio-sensitizing effect.
Based on the available limited information, it is conceivable that interaction may occur with other drugs which are metabolised via the cytochrome CYP3A4. Concurrent administration of Vinorelbine tartrate with an inhibitor of this metabolic pathway may cause an earlier onset and/or increased severity of side effects.
As vinca-alkaloids are known as substrates for P-glycoprotein and in the absence of specific study, caution is recommended when Navelbine is used with strong inhibitors or inducers of cytochrome CYP3A4. Hence, the use of this medicine with phenytoïn, fosphenytoïn, itraconazole or posaconazole is not recommended. As CYP3A4 is mainly involved in the metabolism of vinorelbine, combination with strong inhibitors of this isoenzyme could increase blood concentration of vinorelbine and combination with strong inducers of this isoenzyme could decrease blood concentration of vinorelbine.
Use of this medicine with live attenuated vaccines is not recommended (for yellow fever vaccine, see Contraindications), because of a risk of generalised vaccine disease (could be fatal). This risk is increased in patients already immunodepressed by their underlying disease. It is recommended to use an inactivated when exists (poliomyelitis).
Exacerbation of convulsions can be observed with phenytoin resulting from the decrease of phenytoin digestive absorption by cytotoxic drug or risk of toxicity enhancement or loss of efficacy of the cytotoxic drug due to increased hepatic metabolism by phenytoin.
With oral anticoagulant, there is an increased thrombotic and haemorrhagic risk in case of tumoral diseases. There is an eventuality of interaction between oral anticoagulants and anticancer chemotherapy. Increased frequency of the INR (International Normalised Ratio) monitoring is required.
Concomitant use with immunosuppressive medicines (ciclosporine, tacrolimus, everolimus, sirolimus) should be taken into consideration because of an excessive immunodepression with risk of lymphoproliferation.
As with all vinca-alkaloids, a concomitant use with itraconazole increases neurotoxicity of vinca-alkaloids due to the decrease of their hepatic metabolism, therefore this combination is not recommended.
The combination of Navelbine with other drugs with known bone marrow toxicity is likely to exacerbate the myelosuppressive adverse effects.

Instruction for use/handling: Handling guidelines: the preparation and administration of Navelbine should be carried out by trained staff. Suitable eye protection, disposable gloves, face mask and disposable apron should be worn. Eventual spillage or leakage should be mopped up.
As with other toxic compounds, caution should be exercised in handling and preparing the solution of Navelbine. Skin reactiins may occur with accidental exposire. The use of gloves is recommended. If the solution of Navelbine contacts the skin or mucosa, immediately wash the skin or mucosa thoroughly with soap and water. It is recommended to infuse Navelbine over 6-10 minutes after dilution in 20-50 ml of normal saline or 5% dextrose solution.
After administration, the vein should be thoroughly flushed with at least 250 ml of isotonic solution.
Navelbine must be given strictly intravenously: it is very important to make sure that the cannula is accurately placed in the vein before starting to infuse Navelbine. If Navelbine extravasates into the surrounding tissue during the administration, considerable local irritation may occur. In this case, the administration should be stopped, the vein flushed with normal saline and the remaining dose administered in another vein. In case of extravasations, to reduce the risk of phlebitis, IV glucocorticoids could be administered immediately.

Store at 2°C - 8°C (in a refrigerator) and protected from light.
Do not freeze.
Navelbine is a clear colourless to pale yellow solution. These slight differences in colour do not affect the quality of the product.
Navelbine should not be diluted in alkaline solutions (risk of precipitation).
In case of polychemotherapy, Navelbine should not be mixed with other agents. Navelbine is not adsorbed or affected by either PVC or clear neutral glass.
After diluting Navelbine in normal saline solution or in 5 % dextrose solution, chemical and physical in use stability has been demonstrated for 8 days at room temperature (20 ± 5°C) or in the refrigerator (2 - 8°C) protected from light, in neutral glass bottle, PVC and vinyl acetate bags. From a microbiological point of view, the preparation for infusion should be used immediately (no longer than 24 h after the preparation).
Shelf-Life: Navelbine must not be used after the expiry date stated on the package.
The product is stable for 3 years.

Cytotoxic Chemotherapy

L01CA04 - vinorelbine ; Belongs to the class of plant alkaloids and other natural products, vinca alkaloids and analogues. Used in the treatment of cancer.

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